Process for the preparation of hydroxybenzene sulfonates of morpholinomethyl aminooxazolidones

ABSTRACT

Anti-microbial and anti-haemmorhagic hydroxybenzene sulfonates of morpholinomethyl 3-amino-2-oxazolidones having the general formula:   IN WHICH R1, R2 and R3 represent members selected from the group consisting of hydrogen, hydroxyl and sulfonic acid are obtained by reacting a compound of the formula:   WITH A SULFONIC ACID OF THE FORMULA: AND REACTING THE PRODUCT WITH 5-NITROFURFURAL.

United States Patent Esteve et al.

[54] PROCESS FOR THE PREPARATION OF HYDROXYBENZENE SULFONATES OFMORPHOLINOMETHYL AMINOOXAZOLIDONES Inventors: Antonio Esteve; Jose M.Esplms, both of Barcelona, Spain [73] Assignees: Laboratories del Dr.Esteve, S.A., Barcelona; Laboratories Espinos y Boflll S.A., Cornelia,Spain [22] Filed: July 25, 1967 [21] Appl.No.: 655,772

OTHER PUBLICATIONS l-leymann et al., Arch. Biochem. Biophys. 73, 366-373, 380- 383 (1958).

Londrillo et al., Boll. Soc. Ital. Biol. Sper. 39 (24), 1682- 1683(1963).

Ishidate et al., J. Pharrn. Soc. Japan 69, 513- 518 (1949).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas ToddAttorney-diamond & Littell s7 7 ABSTRACT Anti-microbial andanti-haemmorhagic hydroxybenzene sul- 1 July 18, 1972 fonates ofmorpholinomethyl 3-amino-2-oxazolidones having the general formula:

in which R R and R represent members selected from the group consistingof hydrogen, hydroxyl and sulfonic acid are obtained by reacting acompound pf the formula:

and reacting the product with S-nitrofurfural.

6 Claims, No Drawings BACKGROUND OF THE INVENTION 1. Field of theInvention The instant invention relates to anti-bacterial compounds witha S-nitrofurfurylidene ring attached to an amino-substitutedhetcrocyclic ring or similar grouping. 2. Description of the Prior ArtNumerous anti-bacterial substances are know wherein a 5-nitrofurfurylidene ring is attached through an imino group to theheterocyclic ring.

It has been know for some time, see for instance Dodd and Stillman, J.Pharmacol. (1944), 82, 11, that derivatives of furan, nitrated in the5-position can exhibit bacteriostatic and bactericidal activity invitro.

U. S. Pat No. 2,416,234 (Stillman, Scott) relates to what may be thoughtof as the simplest of such compounds, in the form of5-nitro-2furaldehyde semicarbazone (Nitrofurazone) This compound is atopical antiseptic against Gram-positive and Gram-negative bacteria.Local sensitivity reactions are, however, frequent and prolonged topicaltherapy increases the risk of sensitization.

Another antibacterial compound (see Hayes, US. Pat No. 2,610,181 andMichels, US. Pat. No. 2,898,335) is Nitrofurantoin, i.e. l-(5-nitro-2-furfurylideneamino)hydantoin J OzN C II=NN--(il O 0 CH2 NH Yetanother compound (see US. Pat No. 2,742,462 and Drake and Hayes, US.Pat. No. 2,759,931) is 3-(5-nitro-2-furfurylideneamino)-2-oxazolidinone(Furazolidone) O2NlOJ'CH=NIII(IJ=O Still another compound with aS-nitrofurfurylidene ring is Furaltadone (Altafur), (see US. Pat No.2,802,002).

While such compounds exhibit bacteriostatic and bactericidal activity,their use is often attended by local sensitivity reactions, and, in somecircumstances, their toxicity can present difiiculties.

SUMMARY OF THE INVENTION This invention relates to new morpholinederivatives of hydroxybenzene sulfonates, in particular morpholinederivatives corresponding to the general formula:

in which R,, R and R; represent hydrogen, hydroxyl radicals of sulfonicgroups attached to certain carbon atoms of the benzene nucleus and to anew process for the preparation of such compounds.

Included among this group of products in inter alia the 2,5-dihydroxybenzene sulfonate of 5-morpholinomethyl-3-(5-niu'ofurfurylidene-amino)-2-oxazolidone, a compound which exhibitsremarkable therapeutic properties in regard to its activity on a largevariety of pathogenic microorganisms and its low toxicity, which is evenlower that that of the other nitrofuran derivatives already described.

In addition to its anti-microbial activity, the aforementioned compoundis also eflective as an anti-haemorrhagic which is important above allwhen it is used either preventively or curatively in veterinarymedicine'for treating chronic respiratory disease and other diseasesafiecting cattle with haemorrhagic complications.

To carry out the process according to the invention, the correspondingbenzylidene derivative of S-morpholinylmethyl-B- aminooxazolidonecorresponding to the formula:

is prepared by the action of alkali on an aqueous suspension of theazole hydroxybenzylidene derivative of ethyl N-( 3-morpholinyl-Z-propanol)-N-carboxylate corresponding to the fonnula:

The benzylidene derivative thus obtained is reacted with a benzenesulfonic acid corresponding to the general formula in which R R and Rare as defined above. Finally, a solution of 5-nitrofurfural is added tothe reaction medium without separating the hydroxybenzene sulfonate ofthe 5- morpholinomethyl-3-benzylideneamino-2-oxazolidone formed, thereaction continuing in such a way that, after a certain period of time,the required product is separated out.

general formula in which R, and R are substituted by two 10 hydroxygroups in 2- and S-positions relative to a sulfonic group, while R is asulfonic acid group in the 4-position.

I on. CH2 OII CH2 CH EXAlVlPLE Preparation of the 2,5-dihydroxybenzenesulfonate of morpholinomethyl-3-( S-nitrofurfurylidene-amino)-2-oxazolidone:

l4.5 g. (0.05 mol.) of5-morpholinomethyl-3-benzylideneamino-Z-oxazolidone are dissolved in 100cc. of hot n-butanol. l 1.5 g. (0.06 mol.) of 2,5-dihydroxybenzenesulfonic acid are then added with stirring to the resulting solution,and the resulting mixture is heated for minutes to 80C. A solution of 7g. (0.05 mol.) of 5-nitrofurfural in 50 cc. of butanol is then added,and the solution thus obtained heated under reflux for minutes. In thisway, a yellow oil is formed which settles at the bottom of the reactionvessel. On cooling, the oil solidifies. The liquid is separated and thepowdered solid washed three times with boiling methanol.

Yield 14 g. Physical and chemical properties:

The product thus obtained is a yellow powder which melts at 2l22l4 C. Itforms a 10 percent by weight solution in water at C. It is far lesssoluble in ethyl alcohol and completely insoluble in most of theconventional organic solvents.

Toxicity:

The I .D as determined on rats to which the product was orallyadministered, is 500 mg/kg. Anti-microbial activity:

Anti-microbial activity on various strains of Staphylococci, Salmonellaand Colibacilli was examined by the diffusion method and by the methodcomprising introduction into the medium. The results are set out in thefollowing tables:

TABLE 1 Sensitivity of various microorganisms to the product obtainedwhich was incorporated in the culture medium:

Strain l OONNN N 026 OOOON N Olll OOONN N O absence of growth; N growthsimilar to that of control plate TABLE [I Activity of the productobtained on various microorganisms by the gelose-diffusion test:

Mi r rg ni m Product obtained discs impregnated with a I00 lg/cmsolution mean inhibition diameter Staphylococci Strain 1 17.4 mm. 5 15.9mm. 7 15.6 mm. Salmonella pollorum Strain l 13.90 mm. 14.00 mm.Colibacilli Strain 026 12.80 mm.

Antihaemorrhagic activity:

The product has a marked haemostatic activity which is apparent when itseffects on bleeding time are observed. These efi'ects can bedemonstrated by determining the average bleeding time of rabbits using avariation of the Roskan method cf. J. Laporte, Au sujet de I'EssaiPharmacologique des Hemostatiques] Chimiotherapie, 3; 62/80 (1961 )1before and after administration of the product. On the other hand, theeffect which the new compound has on the mean bleeding time of rabbitsis proportional to the quantity of product administered. Thus, it wasnoticed that the administration of 3.5 mg/kg. of product to a group tosix rabbits produces an average decrease in the mean bleeding time of 18percent. When administered in a dose of 7 mg/kg., the product producesan average decrease in the mean bleeding time of 33 percent and one of40% when administered in a dose of 14 mg/kg.

Applications:

The product obtained by the process according to the invention may beused in therapy for treating infections caused by gram-positive andgram-negative microorganisms. it is particularly effective in thetreatment of infections caused by staphylococci.

It may also be used in veterinary medicine for treating bacterialinfections and is particularly suitable for use in the preventive orcurative treatment of chronic respiratory disease affecting poultry andof cattle diseases accompanied by haemorrhagic complications.

The doses will be governed by the form of administration, the weight ofthe animal and the seriousness of the infection.

The product may be administered if desired in the form of a compositioncomprising the product and a pharmaceuticallyacceptable carrier, bymixing it with the feed or by dissolving it in drinking water or finallyby parenteral injection.

It will be appreciated that the embodiment described has been givenabove all by way of example and that it may be modified in numerous wayswithout departing from the scope of the invention.

We claim:

1. A method for preparing a compound of the formula /O CH2CII R2 I R1SO3NH C 2 CH2 R; I

CH CH un-nar in which R is selected from the group consisting ofhydrogen and sulfonic acid and R and R each represent a hydroxyl whichconsists essentially in reacting a compound of the for- /O CHr-(IEH CIDin which R, R and R are as defined above, treating the resultant productwithout separation with S-nitrofmfural at reflux to give a finalproduct, and isolating the final product.

2. A method according to claim 1 wherein said sulfonic acid is2,5-dihydroxybenzene sulfonic acid.

3. A method according to claim 1 wherein the sulphonic acid is2,5-dihydroxybenzenel ,4-disulfonic acid.

4. A method according to claim 1 wherein said reaction in non-aqueousmedium is carried out at a temperature of from 70 to C.

5. A method according to claim 2 wherein 5-morpholinomethyl-3-benzylidene amino-2-oxazolidone is reacted with2,5dihydroxybenzene sulfonic acid at a temperature of from 70 to 120 C.

6. A method according to claim 2 wherein said non-aqueous medium isn-butanol.

2. A method according to claim 1 wherein said sulfonic acid is2,5-dihydroxybenzene sulfonic acid.
 3. A method according to claim 1wherein the sulphonic acid is 2,5-dihydroxybenzene-1,4-disulfonic acid.4. A method according to claim 1 wherein said reaction in non-aqueousmedium is carried out at a temperature of from 70* to 120* C.
 5. Amethod according to claim 2 wherein 5-morpholinomethyl-3-benzylideneamino-2-oxazolidone is reacted with 2,5-dihydroxybenzene sulfonic acidat a temperature of from 70* to 120* C.
 6. A method according to claim 2wherein said non-aqueous medium is n-butanol.